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Gene Variants That Help Control HIV Infection

Scientists have uncovered genetic clues to explain why some
people infected with HIV-1 have lower levels of virus in their
blood and ultimately progress to AIDS more slowly.

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When a person is first infected with HIV-1, the virus replicates
quickly before the immune system steps in to control the infection.
The amount of virus in the blood, the "viral load," is
checked by the immune system and reaches a steady level called
a "set point." At this stage, before symptoms develop,
the viral load can vary between people by up to 100,000-fold.
In general, the lower the viral load set point the longer the
immune system can work properly to fight off other infections
and the slower the progression to AIDS.

An international team of researchers led by Dr. David Goldstein
of Duke University searched for genetic markers that could explain
the huge variation in viral load set point among people infected
with HIV. Their work was funded by NIH's National Institute of
Allergy and Infectious Diseases (NIAID).

From a pool of 30,000 HIV-positive people, the scientists chose
DNA samples from 486 people whose viral load set points had been
carefully and accurately measured many times. They applied the
DNA samples to gene chips containing more than 555,000 human
gene variants that differ by a single nucleotide called single
nucleotide polymorphisms (SNPs).

In the online edition of Science on July 19, 2007,
the research group reported the discovery of SNPs that can explain
nearly 15% of the variation in viral load set point among infected
people. The strongest association occurred within a stretch of
DNA containing a human retrovirus that was incorporated into
the genome a long time ago but no longer produces infectious
virus. People with this variant also frequently had a rare immune
gene, called HLA-B*5701, near the SNP. The gene codes for a protein
expressed on immune cells that is known to play an important
role in clearing HIV-infected cells.

A second significant variant associated with lower viral load
set point was found in an immune gene called HLA-C. People with
this variant appear to make more HLA-C protein than people without
the variant. To protect itself from the immune system, HIV can
inhibit the expression of two related immune proteins that recognize
virus-infected cells and help eliminate them from the body. However,
scientists believe that HIV cannot similarly reduce HLA-C levels.

"If scientists could design a vaccine to enhance HLA-C-mediated
immune responses," Dr. Goldstein says, "they might
be able to hit HIV at a vulnerable point."

The research team also found variants in a third area that were
linked to disease progression. This first genome-wide picture
of host responses to HIV provides new avenues for the development
of vaccines and improved HIV therapies.